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DOI: 10.3748/wjg.v21.i22.6794
Prognostication and response assessment in liver and
pancreatic tumors: The new imaging
Riccardo De Robertis, Paolo Tinazzi Martini, Emanuele Demozzi, Gino Puntel, Silvia Ortolani, Sara Cingarlini,
Andrea Ruzzenente, Alfredo Guglielmi, Giampaolo Tortora, Claudio Bassi, Paolo Pederzoli, Mirko D’Onofrio
Riccardo De Robertis, Emanuele Demozzi, Gino Puntel, Mirko
D’Onofrio, Department of Radiology, Verona Comprehensive
Cancer Network, G.B. Rossi Hospital, University of Verona,
37134 Verona, Italy
Paolo Tinazzi Martini, Department of Radiology, Casa di Cura
Pederzoli, 37019 Peschiera del Garda, Italy
Silvia Ortolani, Sara Cingarlini, Giampaolo Tortora, Depart­
ment of Oncology, Verona Comprehensive Cancer Network, G.B.
Rossi Hospital, University of Verona, 37134 Verona, Italy
Andrea Ruzzenente, Alfredo Guglielmi, Department of
Hepato-Biliary Surgery, Verona Comprehensive Cancer Network,
G.B. Rossi Hospital, University of Verona, 37134 Verona, Italy
Claudio Bassi, Department of Pancreatic Surgery, Verona
Comprehensive Cancer Network, G.B. Rossi Hospital, University
of Verona, 37134 Verona, Italy
Paolo Pederzoli, Department of Pancreatic Surgery, Casa di Cura
Pederzoli, 37019 Peschiera del Garda, Italy
Author contributions: All authors contributed equally to this
work; Tinazzi Martini P, Ruzzenente A, Guglielmi A, Cingarlini
S, Tortora G, Bassi C, Pederzoli P and D’Onofrio M designed
the research; Demozzi E, Puntel G and Ortolani S performed the
research and analyzed the data; and De Robertis R, Demozzi E
and Puntel G wrote the paper.
Conflict-of-interest: The authors declare no potential conflict of
interest.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Correspondence to: Riccardo De Robertis, MD, Department
of Radiology, Verona Comprehensive Cancer Network, G.B.
Rossi Hospital, University of Verona, Piazzale L.A. Scuro 10,
37134 Verona, Italy. riccardo.derobertis@hotmail.it
Telephone: +39-45-8124301
Fax: +39-45-8027490
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ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2015 Baishideng Publishing Group Inc. All rights reserved.
EDITORIAL
Received: January 28, 2015
Peer-review started: January 28, 2015
First decision: March 10, 2015
Revised: March 25, 2015
Accepted: May 2, 2015
Article in press: May 4, 2015
Published online: June 14, 2015
Abstract
Diffusion-weighted imaging (DWI), dynamic contrast-
enhanced magnetic resonance imaging (DCE-MRI) and
perfusion computed tomography (CT) are technical
improvements of morphologic imaging that can
evaluate functional properties of hepato-bilio-pancreatic
tumors during conventional MRI or CT examinations.
Nevertheless, the term “functional imaging” is
commonly used to describe molecular imaging
techniques, as positron emission tomography (PET)
CT/MRI, which still represent the most widely used
methods for the evaluation of functional properties of
solid neoplasms; unlike PET or single photon emission
computed tomography, functional imaging techniques
applied to conventional MRI/CT examinations do not
require the administration of radiolabeled drugs or
specific equipments. Moreover, DWI and DCE-MRI can
be performed during the same session, thus providing a
comprehensive “one-step” morphological and functional
evaluation of hepato-bilio-pancreatic tumors. Literature
data reveal that functional imaging techniques could
be proposed for the evaluation of these tumors before
treatment, given that they may improve staging and
predict prognosis or clinical outcome. Microscopic
changes within neoplastic tissues induced by treatments
can be detected and quantified with functional imaging,
therefore these techniques could be used also for post-
treatment assessment, even at an early stage. The
aim of this editorial is to describe possible applications
of new functional imaging techniques apart from
6794 June 14, 2015|Volume 21|Issue 22|
 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors
molecular imaging to hepatic and pancreatic tumors
through a review of up-to-date literature data, with
a particular emphasis on pathological correlations,
prognostic stratification and post-treatment monitoring.
Key words: Diffusion magnetic resonance imaging;
Perfusion imaging; Hepatocellular carcinoma; Liver
neoplasms; Pancreatic neoplasms
© The Author(s) 2015. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Diffusion-weighted imaging and perfusion
imaging could add functional information to the
morphological evaluation of hepatic and pancreatic
tumors. Diffusion-weighted imaging findings seem to be
correlated with pathological features and could predict
the clinical outcome of hepatocellular carcinomas
and pancreatic tumors, especially neuroendocrine
neoplasms. Apparent diffusion coefficient quantification
and perfusion techniques can be of value for the
evaluation of response to ablative treatments, loco-
regional therapies and anti-angiogenic therapies, even
at an early stage.
De Robertis R, Tinazzi Martini P, Demozzi E, Puntel G, Ortolani
S, Cingarlini S, Ruzzenente A, Guglielmi A, Tortora G, Bassi
C, Pederzoli P, D’Onofrio M. Prognostication and response
assessment in liver and pancreatic tumors: The new imaging.
World J Gastroenterol 2015; 21(22): 6794-6808 Available from:
URL: http://www.wjgnet.com/1007-9327/full/v21/i22/6794.htm
DOI: http://dx.doi.org/10.3748/wjg.v21.i22.6794
INTRODUCTION
Functional imaging techniques include different methods
that can detect or measure changes in metabolism,
blood flow, and chemical composition. This group
included both molecular imaging methods, as positron
emission tomography (PET)-computed tomography
(CT)/magnetic resonance imaging (MRI) or single
photon emission computed tomography (SPECT),
and radiological techniques, as diffusion-weighted
imaging (DWI), dynamic contrast-enhanced MRI
(DCE-MRI) and perfusion CT (pCT). Functional imaging
techniques are technical improvements of conventional
morphological techniques that can provide both
qualitative and quantitative information on hepato-
[1-3]
bilio-pancreatic tumors , being therefore similar to
molecular imaging techniques. Functional techniques
can be performed during conventional imaging
evaluations as CT or MRI, therefore they describe both
morphological and functional features of solid tumors;
moreover, they do not need radiolabeled agents as
18
fluorodeoxyglucose ( F-FDG) or specific equipments.
DWI evaluate the random diffusion of water mole­
cules: biological tissues with high cellular density
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or altered cellular membranes will present diffusion
restriction, which is depicted as signal hyperintensity
areas on high b-value DW images and hypointensity
on the apparent diffusion coefficient (ADC) maps;
ADC measurement can also quantify water molecules’
diffusion. As dedifferentiation or therapies may induce
microscopic changes in neoplastic tissues that could
modify water molecules’ diffusion, DWI can distinguish
between different degrees of malignancy and can be
also proposed for post-treatment monitoring. More­
over, DWI can be performed in a single session with
DCE-MRI, thus providing a comprehensive “one-step”
morphological and functional evaluation of hepato-
bilio-pancreatic tumors.
Perfusion imaging techniques evaluate changes
in signal intensity (DCE-MRI) or density (pCT) after
contrast medium injection, being therefore able to
assess microvascularization through the evaluation
of the dynamics of contrast medium distribution from
vessels to the neoplastic tissue. Perfusion parameters
are therefore theoretically good candidates for the
evaluation of microscopic vascular differences between
lesions with different pathological grade and for the
assessment of treatment response, especially after
chemoembolization or during treatments with anti-
angiogenic drugs.
This editorial analyzes up-to-date literature data
regarding the application of functional imaging
tech­niques, apart from molecular imaging, to hepatic
and pancreatic tumors, with particular emphasis on
correlations to pathological features, prognostic stra­
tification and therapeutic response assessment.
FUNCTIONAL IMAGING TECHNIQUES:
TECHNICAL BASES
[4]
In 1965 Stejskal and Tanner developed a modified
T2-weighted MR sequence for the detection of water
molecules’ diffusion. DWI enables the visualization
of Brownian random motions of water molecules
in the extracellular, intracellular, and intravascular
[5]
spaces . DWI provides information on tissue cellu­
larity and integrity of cell membranes, since the
degree of restriction to water diffusion in biological
tissues is inversely correlated to these features .
[6-9]
Restricted diffusion is present in tissues with narrowed
extracellular spaces as a consequence of a high cellular
density, which increases the number of hydrophobic
cellular membranes, whereas in cystic or necrotic
[10]
lesions water diffusion is relatively ‘‘free’’ . The b value
is a technical parameter that regulates the sensitivity
of this sequence to water molecules’ diffusion.
Generally, both low and high b values are used for DWI
examination; nevertheless, the choice of the b value
may vary from institution to institution. The intravoxel
incoherent motion (IVIM) model is an advanced DWI
[11,12]
technique developed by Le Bihan that enables a
separate quantitative assessment of all the microscopic
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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors
translational motions that contribute to DWI signal. In
biological tissues, these motions are represented by
the molecular diffusion of water, expressed by diffusion
(D) and pseudodiffusion (D*), and the perfusion effect
caused by blood circulation in the capillary network
(perfusion fraction - f). IVIM, therefore, can evaluate
perfusion features without the need of contrast medium
injection. Multiple b values must be used for IVIM
evaluation.
DCE-MRI was developed to assess myocardial
and pulmonary blood flow. This technique requires
the intravenous injection of a gadolinium-based
contrast agent, followed by rapid serial signal intensity
measurements while the con­trast agent enters
tumor arterioles, passes through capil­lary beds and
washes out of the tumor. Technical improvements
have shortened the acquisition time and have led to
the development of three-dimensional sequences,
which replaced single-section examinations: as a
consequence, DCE-MRI can be applied to abdominal
imaging. The contrast kinetics features assessed by
DCE-MRI reflect tissue perfusion, the concentration-
time curve in the arterial input vessel, the capillary
surface area, the permeability and the volume of the
extracellular extravascular space. As a consequence,
several metrics can be derived from DCE-MRI
trans
evaluation: the volume transfer constant (K ), the
fractional volume of the extravascular-extracellular
trans
space (ve), the rate constant (Kep, where Kep = K /
ve), the fractional volume of the plasma space (vp),
the area under the contrast agent concentration-time
[13]
curve (AUC) . In 1999, a consensus opinion agreed
[13]
to standardize the terminology of DCE-MRI studies
trans
and selected AUC60 and K as the preferred end
points in clinical trials involving anti-angiogenic
[13,14]
drugs . Nevertheless, DCE-MRI end points can be
tailored to the specific drug involved in the trial.
Perfusion CT has the same physical bases of
DCE-MRI, as it is based on the evaluation of temporal
changes in tissue density following intravenous admi­
nistration of iodine contrast medium. By rapid sequential
acquisitions during contrast medium passage, pCT
allows the quantification of tissues’ vascularity. Per­
fusion can be quantified using mathematical modeling
techniques (mainly the compartmental and the
deconvolution analysis) that use data derived both
[15-17]
from the tissue and the vascular system . The
analytical methods and the acquisition protocols vary
from institution to institution and between commercial
vendors, leading to poor standardization. Many different
metrics can be directly or indirectly derived from pCT
studies: blood flow (BF), representing the flow rate
through vasculature; blood volume (BV), representing
the volume of flowing blood; mean transit time (MTT),
representing the average time taken to travel from
arteries to veins; perfusion, representing the flow
rate through vasculature; permeability surface (PS),
representing the total flux from plasma to interstitial
space; peak enhancement image (PEI), representing
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the maximum enhancement in a tissue region of inte­
rest; and time to peak (TTP), defined as the time from
the arrival of the contrast medium in major arterial
vessels to the peak enhancement). Other than poor
standardization, another important drawback of pCT is
the high radiation dose, even though technical improve­
ments have recently led to the development of low-
[18]
dose pCT examination protocols .
CORRELATION WITH PATHOLOGICAL
FINDINGS AND PROGNOSTIC
STRATIFICATION
Primary liver tumors
The prognosis and management of hepatocellular
carcinoma (HCC) depend on size, degree of dedifferen­
tiation, presence of vascular invasion and intrahepatic
[19]
metastases . As advanced and poorly differentiated
HCCs have a significantly worse prognosis than well
and moderately differentiated lesions after surgical
[20]
resection , preoperative staging and prognostic
prediction play an important role, eventually sug­
gesting wider surgical clearance margins and closer
post-treatment surveillance.
As the pathological grade of HCC depends on
[21]
cellular and structural atypia , increasing cellular
density, nuclear-to-cytoplasmic ratio, and architectural
complexity accompanying dedifferentiation may
cause water diffusion restriction. DWI features can
be assessed both with a visual (qualitative) and a
quantitative analysis through ADC measurement. An
[22]
et al reported a linear correlation towards higher
grades in HCCs showing diffusion restriction: the
combination of absence of diffusion restriction (defined
as no hyperintensity on high b-value DW images) and
no arterial enhancement at conventional contrast-
enhanced MRI in predicting well differentiated HCCs
had a 100% positive predictive value. The multistep
nature of HCC dedifferentiation probably necessitates
a quantitative approach rather than a simple visual
analysis. Details on the main published studies
regarding ADC measurement and correlations with the
pathological grade of HCCs are reported in Table 1.
Overall, literature data show that HCC dedifferentiation
tends to be associated with a decrease of the ADC
[23-29]
value, despite differences between studies . Apart
from the direct correlation with the pathological grade,
[29]
Nakanishi et al found that ADC quantification might
have a clinical prognostic value, being significantly
lower in patients with early recurrence after surgery
than in those without early recurrence. One important
aspect dealing with ADC measurement is the choice
of the region of interest (ROI), given that a “whole-
tumor” ROI can be irrespective of lesion heterogeneity:
as previously mentioned, necrotic areas have a
relatively free diffusion and should be avoided during
ROI placement because they may falsely increase the
ADC value; ADC measurement should be therefore per­
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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors

would be ideal for the prediction of the pathological

Table 1 Data derived from the main published studies that
have tested correlations between apparent diffusion coefficient grade and clinical behavior of HCCs, but literature
values and pathological grade of hepatocellular carcinomas data at this regard are relatively poor. One single
[37]
study reported a significant negative correlation
Study Number of b values mean ADC value between the standardized uptake value (SUV) derived
2 -3 2
patients (s/mm ) (× 10 mm /s) 18 trans
from F-FDG PET/CT and K in advanced HCCs.
Nasu et al[23] 99 0, 500 1.45 (WD); 1.46 (MD); Some more studies have been conducted with pCT:
1.36 (PD) [38]
while Ippolito et al did not report any significant
Piana et al[24] 99 0, 500 1.29 (WD); 1.22 (MD);
1.21 (PD) correlation between pCT-derived parameters and
[39]
Saito et al[25] 32 100, 800 1.25 (WD); 1.12 (MD); pathological grade, Sahani et al found that well-
1.13 (PD) differentiated HCCs had significantly higher perfusion
Muhi et al[26] 73 500, 800 0.91 (WD); 0.71 (MD); values than less differentiated lesions. Yang et al
[40]

0.68 (PD)
Nishie et al[27] 80 0, 500, 1000 1.21 (WD); 1.14 (MD);
0.76 (PD)
Heo et al[28] 27 0, 1000 1.20 (WD); 1.10 (MD);
0.90 (PD)
Nakanishi et al[29] 44 0, 50, 1000 1.29 (MD); 1.07 (PD)
ADC: Apparent diffusion coefficient; WD: Well differentiated; MD:
Moderately differentiated; PD: Poorly differentiated.
formed only on solid areas showing diffusion restriction.
Studies regarding IVIM imaging reported interesting
[30]
results. Woo et al found that the D value (diffusion)
quantification had significantly higher AUC than ADC
measurement for the differentiation between high-
grade and low-grade HCCs. Moreover, the percentage
of arterial enhancement depicted at conventional
contrast-enhanced MRI, which is directly linked to the
degree of dedifferentiation of HCCs, was correlated
with IVIM-derived f value (perfusion fraction).
As previously mentioned, the prognosis of patients
with HCC depends also on other pathological features:
DWI has been tested for the detection of malignant
features of HCC, as vascular involvement or intra­
hepatic metastases. It has been reported that ADC
measurement has a high sensitivity and specificity
(reaching up to 93.5% and 78.6%, respectively) for
[31,32]
the prediction of microvascular involvement . Portal
[33]
vein involvement precludes most curative options ,
but its diagnosis may be hampered by the presence of
a non-neoplastic thrombus in a cirrhotic liver. Few and
controversial papers have been published regarding
the ability of DWI in distinguishing malignant from
[34]
non-malignant thrombi: Catalano et al reported that
most neoplastic thrombi were isointense to the primary
tumor on DWI, whereas all bland thrombi were
hypointense; it must be noted that blood degradation
products present variable T2 signal prolongation and
water diffusivity, therefore false-positives may be
[35]
encountered at DWI . Satellite nodules are important
determinants of patients’ prognosis and influence the
therapeutic approach. The high accuracy of DWI in
detecting small HCCs, even smaller than 1 cm, may
be assumed to be applicable to intrahepatic HCC
[36]
metastases .
Arterial blood supply tends to increase during
hepatocarcinogenesis. Perfusion imaging techniques
reported that pCT could quantitatively assess the
blood supply and particularly its distribution during
hepatocarcinogenesis, with statistically significant
correlations between BF, hepatic arterial perfusion
(HAP) and microvascular density (MVD).
Few experiences, mainly focused to a qualitative
visual assessment of DW images, have been reported
[41]
regarding cholangiocarcinoma (CCC). Cui et al
found an inverse correlation between the pathological
grade and ADC values; Park et al
[42]
reported that
the addition of DWI to conventional sequences might
improve the pre-operative assessment of hilar CCC,
increasing the sensitivity for the evaluation of tumor
extent along the bile ducts and liver invasion, thus
improving T stage, a parameter that is directly related
to prognosis.
Pancreatic tumors
Although the prognosis of patients with pancreatic
ductal adenocarcinomas (PDACs) is related to the
pathological grade, treatment choice mainly relies on
clinical stage. Surgical resection is the only curative
treatment for this neoplasm, therefore the pre-
operative prediction of the pathological grade may
have a smaller importance for PDAC management as
compared to other pancreatic tumors.
Some studies have tried to correlate DWI findings
with the pathological grade, but results are contro­
versial
[43-45]
. Details on the most relevant published
studies are reported in Table 2. Overall, low-grade
PDACs tend to present low ADC values
[43-45]
, but it still
not clear which histological feature mainly contributes
to diffusion restriction. Wang et al
[43]
and Muraoka
et al
[46]
reported that tumors with limited glandular
formation and dense fibrosis (i.e., paucicellular
tumors) had lower ADC values as compared to well-
differentiated lesions characterized by neoplastic
tubular structures; moreover, PDACs with dense
fibrosis showed significantly lower ADC values than
those with loose fibrosis. Fibrosis may be therefore the
key factor contributing to diffusion restriction in PDACs,
but these findings have not been confirmed by other
[47]
studies: particularly, Klauss et al reported that the
difference between the IVIM-derived D value (diffusion)
of moderate and severe fibrosis PDACs was significant,
but the cellular complexes surrounded by fibrosis

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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors

showed transient decreases in signal intensity [signal

Table 2 Data derived from the main published studies that
have correlated apparent diffusion coefficient quantification ratio (SR): 6.9%-55.7%]; high SR (cut-off 22%)
with the pathological grade of pancreatic ductal adenocar­ significantly correlated with higher disease stage and
cinomas and neuroendocrine tumors presence of nodal metastases; patients with high SR
had significantly short overall survival.
Study n b values Histotype mean ADC value
Pancreatic neuroendocrine tumors (PanNETs) can
2 -3 2
(s/mm ) (× 10 mm /s)
be divided into well/moderately differentiated and
Wang et al[43] 21 0, 500 PDAC 2.10 (WD-MD);
1.46 (PD)
poorly differentiated lesions and their mitotic rate
Legrand et al[44] 22 Multiple1 PDAC 1.43 (WD); based on the quantification of the mitotic index (Ki67%)
1.94 (MD-PD) can distinguish three categories: G1, with a Ki67 ≤
Rosenkrantz et al[45] 30 0, 500 PDAC 1.78/1.75 (WD-MD); 2%, G2 (Ki67 3%-20%), and G3 (Ki67 > 20%) .
[57]

1.69/1.62 (PD)2
Wang et al[58] 18 0, 50, 500 PanNET 1.75 (G1); 1.00 (G3)
Jang et al[59] 20 0, 800 PanNET 1.48 (G1-G2);
1.04 (G3)
Hwang et al[60] 44 Multiple3 PanNET 1.31 (G1);
1.08 (G2-G3)
1
50, 200, 400, 600, 800 s/mm2; 2Two readers; 30, 25, 50, 75, 100, 150, 200,
500, 800, 1000 s/mm2. n: Number of patients; ADC: Apparent diffusion
coefficient; PDAC: Pancreatic ductal adenocarcinoma; WD: Well diffe­
rentiated; PanNET: Pancreatic neuroendocrine tumor; MD: Moderately
differentiated; PD: Poorly differentiated.
might provide more structural limitations than fibrosis
[44]
alone. Legrand et al reported that mean ADC values
did not significantly differ between tumors having <
50% and those having > 50% of fibrotic stroma, or
between tumors containing dense fibrosis and those
containing loose fibrosis. Similarly, Rosenkrantz et al
[45]
reported no associations between ADC values and
“adverse” pathological features as poor differentiation.
Some authors have proposed a more practical role for
functional imaging, testing correlations with clinical
features as tumor stage or survival. Hayano et al
[48]
reported a significant negative correlation between ADC
values, size and number of metastatic lymphnodes;
PDACs with low ADC values presented also a high
tendency to show portal system and extra-pancreatic
nerve plexus invasion. The comparison of CT and DWI
[49]
performed by Fukukura et al , instead, reported that
only CT findings might be associated with the clinical
behavior of PDACs. Some studies focused on the
application of DWI to the detection and characterization
of liver metastases from PDAC and reported high
sensitivity and specificity using DWI alone
[50]
or DWI
plus other sequences
[51-53]
: imaging features derived
from conventional MR sequences should be always
taken into account because of the possible presence of
DWI false-positives.
Well-differentiated PDACs have a higher micro­
vascular density as compared to less differentiated
[54]
tumors ; perfusion imaging should therefore theore­
tically be able to identify well-differentiated PDACs,
which have better prognosis than poorly differentiated
lesions. It has been reported that pCT-derived PEI and
BV values could identify high grade PDACs with 100%
[55] [56]
specificity and 75% accuracy . Ueno et al reported
that DCE-MRI might predict the survival of patients
with advanced PDAC: all patients included in this study
Several treatment options, ranging from surgery to
systemic therapy or loco-regional treatments, have
been proposed for PanNETs according to their grade of
differentiation. The histological grade plays therefore a
key role in the clinical management of PanNETs; many
studies have been conducted regarding the application
of functional imaging techniques to PanNETs, apart
from nuclear imaging techniques. Details regarding
ADC measurements correlations with the grade of
differentiation are reported in Table 2. Overall, it seems
that ADC values are correlated with the Ki67 labeling
index: G3 PanNETs tend to present lower mean ADC
[58-60]
values compared to well-differentiated PanNETs .
As for PDACs, staging plays a fundamental for
treatment planning and prognostication of PanNETs.
In most cases, liver metastases from PanNETs are
hypervascular; nevertheless, in some cases they
can be iso- or hypovascular and therefore difficult to
detect and correctly characterize using conventional
imaging techniques. Moreover, heterogeneity of liver
[61]
metastases has been reported . DWI is a good
functional technique for the detection of PanNET liver
metastases, with 71% sensitivity and 85%-100%
specificity, equal or even higher than T2-weighted
[62,63]
and contrast-enhanced images . In a study that
evaluated the role of DWI in the differentiation of
hemangiomas from other hypervascular liver lesions,
the mean ADC value of NETs metastases was found
-3 -3 2 [64]
to be 1.43 × 10 ± 0.39 × 10 mm /s , slightly
higher than that reported by Schmid-Tannwald (1.23
-3 -3 2 [65]
× 10 ± 0.31 × 10 mm /s) . Nevertheless, MR
features derived from conventional sequences should
be always taken into account, due to a wide overlap
in ADC values among different liver lesions. DWI can
also obtain images from the entire body in one single
acquisition (whole-body diffusion-weighted imaging
[66]
- WBDWI). Cossetti et al reported two cases of
NETs with distant metastases (bone and mediastinal
lymphnodes) discovered by WBDWI and confirmed by
[67]
Octreoscan. Etchebehere et al compared WBDWI
68
with Ga-DOTATATE PET-CT and 99mTc-HYNIC-
Octreotide SPECT-CT: WBDWI had a similar accuracy
when compared to molecular imaging techniques
for lung and liver lesions, while showed a higher
[68]
false-negative rate for bone lesions. Schraml et al
reported that PET-CT and WBDWI had comparable
overall detection rates for NETs metastases but

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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors
significantly differed in organ-based detection rates with
superiority of PET-CT for lymph node and pulmonary
lesions and of WBDWI for liver and bone metastases.
Experimental applications of pCT to PanNETs
[69]
reported interesting results. Rodallec et al and
[70]
D’Assignies et al reported that pCT features were
correlated with MVD; moreover, BF values of benign
PanNETs were higher than those of uncertain behavior
tumors and carcinomas, and significant correlations
were reported between BF, MTT and proliferation
index, microscopic vascular neoplastic involvement
and presence of nodal or liver metastases. Regarding
[71]
staging, Ng et al reported that BF and hepatic
arterial fraction were significantly higher in liver
metastases from PanNETs than in healthy liver,
thus reflecting an increased arterial blood supply to
metastatic lesions; opposite relationships were found
[72]
for MTT and PS. Guyennon et al reported that pCT
could provide additional information in respect to
conventional CT; particularly, despite both hyperva­
scular and hypovascular metastases presented higher
hepatic arterial perfusion index as compared to the
background liver, mean BF and BV values were higher
in hyperdense metastases compared with hypodense
lesions. All liver metastases showed higher BF, BV, PS
and hepatic arterial perfusion index as compared to
the background liver.
Functional parameters derived from pCT may
therefore be useful for the characterization of suspect
PanNET liver metastases when they present atypical
morphological features, as hypovascularity.
Well- and poorly-differentiated PanNETs present
[73]
different DCE-MRI features. Bali et al reported that a
signal intensity - time curve similar to that of the aorta
was typical of well-differentiated PanNETs, while a curve
characterized by a slow enhancement was present in
non well-differentiated PanNETs, but also in PDACs.
Moreover, a positive correlation was observed between
the MVD and the distribution factor, which reflects the
volume fraction of the tissue that is accessible to the
contrast agent (i.e., the plasma and the extravascular
[74]
extracellular space). Kim et al found a significant
difference in the perfusion characteristics of well-
differentiated PanNETs and neuroendocrine carcinomas:
trans
K values, representing tissue blood flow, were
significantly lower in G3 tumors. Interestingly, the
trans
mean K of neuroendocrine carcinomas was higher
than that of PDACs, thus reflecting the true histological
features of PanNETs: even if poorly differentiated, they
present higher MVD as compared to PDACs.
DCE-MRI has been tested for PanNETs staging.
[75]
Koh et al found three different patterns of contrast
enhancement for neuroendocrine hepatic metastases,
with specific perfusional parameters. DCE-MRI is
therefore potentially able to categorize metastases
on the basis of their vascular characteristics, with
prognostic and therapeutic consequences. Armbruster
[76]
et al reported that arterial flow fraction and
intracellular uptake fraction have a high diagnostic
WJG|www.wjgnet.com
accuracy for the distinction between NET liver
metastases and normal hepatic tissue. DCE-MRI
parameters are also partially correlated to SUVs derived
18 68
from F-FDG- and Ga-DOTA-Tyr(3)-octreotate (68Ga-
[77]
DOTATATE-) PET/CT .
RESPONSE TO TREATMENTS
Primary liver tumors
Loco-regional therapies as percutaneous or intra-
operative ablation techniques [radiofrequency ablation
(RFA), microwaves, irreversible electroporation or
transarterial chemoembolization (TACE) and radioem­
bolization (TARE)], have significantly contributed
[78]
to the control of unresectable localized HCCs . As
these therapies may be repeated and interchangeably
applied, early assessment of treatment response
is crucial. Response Evaluation Criteria In Solid
Tumors (RECIST) criteria are not applicable to HCC,
as both loco-regional treatments and systemic
therapy generally result in tumor necrosis rather than
shrinkage. The European Association for the Study
of Liver Diseases has proposed to assess response to
loco-regional treatments by assessing the decrease in
viable tumor volume, seen as a decrease in contrast-
enhancing areas at conventional contrast-enhanced
[79]
CT/MRI . However, the differentiation of viable tissue
from treatment-induced changes as inflammation or
granulation tissue can be difficult, as these non-tumoral
[80,81]
changes can present contrast enhancement .
DWI and perfusion imaging techniques may have a
potential role in the differentiation of viable tumor from
treatment-induced necrosis. Viable neoplastic areas
present high cellularity with intact cell membranes
and show high vascularization; conversely, treatment-
induced necrotic and inflammatory changes present
a reduced cellular density, an increased membrane
permeability and poor vascularization.
Radiofrequency ablation (RFA) induces coagulative
[82]
necrosis in tumor tissues. Lu et al reported that
the ADC values of HCCs successfully treated with RFA
showed a predictable evolution and might help radio­
logists to monitor tumor response, being significantly
[83]
high starting from 1 mo after RFA. Ippolito et al
reported that pCT enabled the assessment of HCC
vascularity after RFA, providing quantitative information
about the presence of arterial vessels within viable
residual neoplastic tissues: in this study, a significant
difference in perfusion, arterial perfusion (AP), and
hepatic perfusion index (HPI) values was found
between treated lesions with residual tumor and those
[84]
successfully treated. Eccles et al reported statistically
significant changes in ADC values of HCCs treated
with radiotherapy (RT): in their study, the baseline
-3 2
median ADC of 1.56 × 10 mm /s increased to 1.89
-3 2 -3 2
× 10 mm /s at RT week one, to 1.91 × 10 mm /s
-3 2
during week two and to 2.01 × 10 mm /s one month
following treatment; early increases of ADC values were
[85]
correlated with sustained tumor response. Kim et al
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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors

Table 3 Data derived from the main published studies that have evaluated apparent diffusion coefficient values before and after
trans-arterial treatments of primary and metastatic liver tumors

Study n b values (s/mm2) ADC before treatment ADC after treatment Histotype Treatment
-3 2 -3 2
(× 10 mm /s) (× 10 mm /s)
Kamel et al[86] 38 0, 500 1.51 1.70 HCC TACE
Sahin et al[87] 74 0, 50, 400, 800 1.10 1.27 HCC TACE
Kamel et al[88] 24 0, 50, 750 1.86 2.13 HCC TACE
Chen et al[89] 20 0, 500 1.56 2.09 HCC TACE
Yuan et al[90] 41 0, 500 2.22 1.42 HCC TACE
Deng et al[98] 6 0, 500 1.30 2.23 HCC TARE
Kamel et al[99] 13 0, 500 1.65 1.95 HCC TARE
Rhee et al[100] 20 0, 500 1.64 1.82 HCC TARE
Mannelli et al[102] 36 0, 50, 500 1.64 1.92 HCC TACE
Kubota et al[103] 25 0, 500 1.271 1.3571/1.2222 HCC TACE
Liapi et al[120] 26 0, 500 1.51 1.79 Metastases (PanNET) TACE
Li et al[121] 26 0, 750 1.31 1.59 Metastases (PanNET) TACE

1
No disease relapse; 2Disease relapse. ADC values are presented as means. n: Number of patients; ADC: Apparent diffusion coefficient; HCC: Hepatocellular
carcinoma; PanNET: Pancreatic neuroendocrine tumor; TACE: Trans-arterial chemoembolization; TARE: Trans-arterial radioembolization.

reported that ADC values and DCE-MRI parameters
acquired before concurrent chemoradiotherapy
correlated with progression-free survival (PFS) and
were valuable in the prediction of the clinical outcome.
The best cutoff values for response prediction of ADC,
trans
K , Kep, and extravascular extracellular volume
-3 2
fraction (ve) were 1.008 × 10 mm /s, 0.108 /min,
-1
0.570 min , and 0.298%, respectively.
Many studies have been conducted on the
application of functional imaging techniques for HCCs
treated with TACE and TARE; the most significant
results are reported in Table 3. Overall, ADC values
tend to increase after TACE, even at an early
[86-89]
evaluation . DWI can reliably assess the efficacy
[90]
of trans-arterial treatments: Yuan et al
differences in the mean ADC values of the necrotic
and vital tumor tissues after TACE (2.22 × 10 ±
-3 2 -3
0.31 × 10 mm /s and 1.42 × 10 ± 0.25 × 10
2 -3
mm /s, respectively); a significant linear correlation
was identified between the ADC value of the entire
area of the treated mass and the extent of tumor
necrosis (r = 0.58; P < 0.001). Mannelli et al
not report differences between conventional MRI
sequences and DWI for the assessment of post-TACE
necrosis, although enhancement decrease on MRI
subtraction images was more significantly correlated
with pathological findings than ADC increase. Although
quantitative analysis of diffusion restriction appears
to be of value in assessing response to TACE, visual
analysis seems to be less accurate: Goshima et al
reported that DW images were significantly less
sensitive than contrast-enhanced images in detecting
residual/recurrent tumor after TACE, and Yu et al
reported that the addition of DW images to contrast-
enhanced images reduced specificity and diagnostic
accuracy in detecting perilesional recurrence. Probably,
the presence of treatment-induced granulation tissue
is the cause of DWI false positives.
[94]
Regarding pCT, Yang et al reported a significant
decrease of the HAP, total liver perfusion (TLP), and
hepatic arterial perfusion index (HAPI) values 4 wk
after TACE.
[95]
Braren et al reported strong correlation between
the extravascular extracellular volume fraction
assessed with DCE-MRI and the percentage of
[96]
residual tumor after TACE. Taouli et al reported that
untreated HCCs had higher arterial fraction and lower
portal/venous hepatic blood flow values than chemo­
embolized HCCs.
90
Trans-arterial yttrium-90 ( Y) radioembolization
(TARE) aims to deliver a high radiation dose to
[97]
HCCs . Although a small study reported a 60%
[98]
increase in the mean ADC value after TARE , other
studies reported less conspicuous ADC increases
[99] [100]
reported (approximately 10%-20%) . Rhee et al reported
that 1-mo response to TARE assessed with DWI
-3
significantly preceded size changes: the mean
-3 -3 -3 2
baseline ADC value (1.64 × 10 ± 0.30 × 10 mm /s)
-3 2
increased to 1.81 × 10 ± 0.37 × 10 mm /s at 1 mo
-3 -3 2
(P < 0.05), and to 1.82 × 10 ± 0.23 × 10 mm /s
at 3 mo (P < 0.05), while the mean tumor size did not
[91]
did significantly modify at 1 or 3 mo. Functional imaging
techniques may be helpful for response prediction to
[101]
trans-arterial treatments. Park et al reported that
IVIM imaging could predict lipiodol uptake: the D*
(pseudodiffusion) value was significantly higher in a
“lipiodol-good uptake” HCC group than in a “lipiodol-
[102]
poor uptake” group. Mannelli et al reported
that ADC quantification could predict response to
[92]
TACE: HCCs with poor/incomplete response (< 50%
necrosis) had significantly lower pre- and post-TACE
ADC values than lesions with good/complete response.
[93] [103]
Kubota et al reported that the percent ADC value
modification after therapy was significantly higher in
non-relapsed HCCs (85.2% ± 12.4%) as compared
to lesions with disease relapse (8.0% ± 56.7%, P <
[104]
0.001). Konstantinidis et al reported that DCE-MRI
could predict treatment outcome after hepatic arterial
infusion (HAI) of floxuridine and dexamethasone (with
or without bevacizumab) in advanced intra-hepatic

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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors

Table 4 Data derived from the main published studies that have correlated functional radiological techniques with response to
systemic therapies of hepatic and pancreatic tumors

Study n Technique Imaging biomarker Histotype Treatment

Lewin et al[107] 12 IVIM f increase HCC sorafenib
Vouche et al[108] 15 DWI ADC increase HCC 90
Y TARE ± sorafenib
Hsu et al[109] 31 DCE-MRI Ktrans decrease HCC sorafenib+metronomic tegafur/uracil
Yopp et al[111] 17 DCE-MRI AUC90/AUC180/Ktrans decrease HCC bevacizumab
Jiang et al[112] 23 pCT BF/BV/PS decrease HCC bevacizumab + cytotoxic agents
MTT increase
Kim et al[113] 10 DCE-MRI/DWI Ktrans/Kep decrease HCC sunitinib
ADC increase
Sahani et al[114] 23 DCE-MRI/DWI Ktrans/Kep decrease HCC sunitinib
ADC increase
Kim et al[123] 35 pCT BF decrease CRC metastases XELOX, FOLFOX, FOLFIRI
Schlemmer et al[124] 24 pCT Perfusion decrease PanNET metastases Tyrosine-kinase inhibitors
Anzidei et al[125] 18 pCT, DWI CP decrease CRC metastases Oxaliplatinum, capecitabine,
ADC increase bevacizumab
De Bruyne et al[127] 19 DCE-MRI AUC decrease CRC metastases Bevacizumab
Vriens et al[129] 23 DCE-MRI Ktrans decrease CRC metastases Cytotoxic therapy
Coenegrachts et al[130] 10 DCE-MRI Kep increase CRC metastases Bevacizumab + FOLFIRI
Deckers et al[126] 20 DWI ADC decrease CRC metastases Chemotherapy
Niwa et al[133] 63 DWI ADC decrease PDAC Gemcitabine
Cuneo et al[134] 12 DWI ADC increase PDAC Chemoradiation
Yao et al[135] 39 pCT BF decrease PanNET Bevacizumab ± everolimus
Miyazaki et al[132] 20 DCE-MRI Distribution volume increase PanNET metastases 90
Y-octretotide

n: Number of patients; IVIM: Intravoxel incoherent-motion diffusion-weighted imaging; f: Perfusion fraction; HCC: Hepatocellular carcinoma; 90Y TARE:
90
Yttrium trans-arterial radioembolization; DWI: Diffusion-weighted imaging; ADC: Apparent diffusion coefficient; DCE-MRI: Dynamic contrast-enhanced
MRI; Ktrans: Volume transfer constant; AUC90, AUC180: Area under the curve at 90 and 180 s; pCT: Perfusion computed tomography; BF: Blood flow; BV:
Blood volume; PS: Permeability surface; MTT: Mean transit time; Kep: Rate constant; CP: Capillary permeability.

CCCs: AUC90 and AUC180 were significantly higher in ≥
3-year survivors than < 3-year survivors.
The advent of anti-angiogenic therapies, including
sorafenib and bevacizumab, greatly expanded treat­
ment options for HCCs. As anti-angiogenic drugs
frequently do not induce tumor shrinkage but acts on
tumor vascularization, functional imaging techniques
may be suitable for the evaluation of patients treated
with these agents. Details regarding the most relevant
studies on treatment assessment by means of func­
tional radiological techniques are reported in Table 4.
Sorafenib, an oral multikinase inhibitor that sup­
presses tumor cell proliferation and angiogenesis, is
so far the only drug that has shown overall survival
[105]
benefit in patients with advanced HCC
represents the standard systemic therapy for patients
with advanced (unresectable and/or metastatic) HCCs
with well-preserved liver function and for intermediate-
stage HCCs with disease progression after local
[106]
treatments . As sorafenib inhibits neovascularization
and decreases tumor vascularity, perfusion parameters
should decrease in responding patients. Nevertheless,
literature data are controversial. Lewin et al
reported a significant f (perfusion fraction) increase in
responders at 2 wk and at 2 mo of sorafenib therapy,
whereas a decrease was noted in non-responders at
[108]
the same time intervals. Vouche et al reported that
90
ADC values did not change 1 and 3 mo after Y TARE
90
or Y TARE plus sorafenib treatments. These results
may be explained by the pleiotropic anti-angiogenic
actions of sorafenib, which destroys tumor vessels
and improves the integrity of basement membranes
of the remaining microvessels, thus leading to less
“water leakage” from the perfusion pool. Modifications
during sorafenib treatment can be assessed also using
[109]
perfusion-imaging techniques. Hsu et al found
trans
good correlations between K values and survival
in patients who received sorafenib plus metronomic
trans
tegafur/uracil therapy: baseline K was higher in
patients with RECIST partial response (PR) or stable
disease (SD) than in those with progressive disease
[110]
(PD). Frampas et al reported a non-significant
decrease in all pCT-derived values between RECIST
non-progressors and progressors treated with sorafenib.
and Although not routinely used in clinical practice,
other anti-angiogenic therapies are on study for HCCs,
including bevacizumab (a monoclonal antibody directed
against vascular endothelial growth factor - VEGF)
and sunitinib (an oral multikinase inhibitor with VEGF-
[111]
receptor as one of its targets). Yopp et al reported
trans
a significant decrease of AUC90, AUC180, and K in
HCCs treated with bevacizumab; time to progression
[107]
inversely correlated with AUC90 and AUC180 changes
(P < 0.05 and P < 0.001). In one study focused on
locally advanced HCCs receiving bevacizumab and
trans
cytotoxic therapy, high pretreatment K identified
[112]
patients with RECIST response to therapy . Sunitinib
trans
seems to induce K and Kep decrease and ADC
[113,114]
increase ; these modifications can be assessed
even at a very early stage (after 2 wk of treatment).

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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors
trans
Moreover, patients with larger K and Kep decrease
might have a favorable clinical outcome; high baseline
trans
K and large decreases of the extracellular volume
fraction were correlated with longer PFS. No significant
changes at DCE-MRI have been reported after van­
[115,116]
detanib treatment . of DCE-MRI-derived endpoints. De Bruyne et al
Liver metastases
Lu et al
[82]
reported that metastatic liver lesions
successfully treated by RFA showed a predictable
evolution of ADC values, with an up-and-down
variation during follow-up. Szurowska et al
[117]
reported
that low pre-treatment ADC values could predict
complete response of colorectal adenocarcinoma
(CRC) liver metastases treated with RFA. Meijerink
et al
[118]
reported that pCT-derived BF distribution
fully paralleled PET/CT images in showing either the
absence or presence of local recurrence after RFA:
high hepatic arterial perfusion (> 50 mL/min per 100
g) and low portal venous perfusion (< 10 mL/min per
100 g) areas represented viable neoplastic tissue.
Marugami et al
[119]
reported that ADC quantification
might be helpful for the early detection of response in
CRC liver metastases treated with HAI chemotherapy
with 5-fluorouracil: ADC increase was significantly
greater in responders than in non-responders.
Chemoembolization induces an increase of ADC
values in PanNET liver metastases
[120-122]
; response to
TACE can be assessed even at an early stage, starting
[122]
from three weeks after treatment . Details on the
main published studies regarding functional imaging
applications after trans-arterial treatments are reported
in Table 3. Functional radiological techniques have
been tested for follow-up evaluations during systemic
treatment of liver metastases; details are reported in
[123]
Table 4. Kim et al reported that pCT-derived BF and
flow extraction product (FEP) could be used as early
response predictors in patients with liver metastases
from CRC, being both significantly different between
responders and non-responders to XELOX, FOLFOX or
FOLFIRI chemotherapy regimens.
[124]
Schlemmer et al reported that metastatic
NETs with good response to tyrosine kinase inhibitors
showed a significant tendency towards lower perfusion
values assessed by pCT as compared to poor respon­
[125]
ders. Anzidei et al reported that both pCT and
DWI could detect therapy-induced (oxaliplatinum,
capecitabine and bevacizumab) modifications in CRC
liver metastases vascularization before significant size
changes became evident: capillary permeability was
significantly higher in lesions with complete and partial
response; moreover, ADC values were significantly
higher in partial response lesions than in patients with
[126]
stable disease. Deckers et al reported that the
increase of ADC values in responding liver metastases
could occur even within days after the start of
chemotherapy; unfortunately, as these changes were
of smaller magnitude than the variability of ADC
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measurement, ADC quantification was not reliable
enough to predict final response at such an early time
point in individual lesions.
Many studies have been conducted with DCE-MRI,
probably as a consequence of the standardization
[127]
reported that bevacizumab therapy could decrease
DCE-MRI-derived AUC in patients with CRC liver
[128]
metastases. Vriens et al reported a large reduction
in DCE-MRI-derived perfusion parameters and glucose
18
metabolic rate at F-FDG PET/CT in CRC metastases
[129]
treated with bevacizumab. The same author
reported also that cytotoxic chemotherapy did not alter
DCE-MRI-derived properties of tumor vasculature.
[130]
Coenegrachts et al reported that a decrease of Kep
allowed early identification of response after 6 wk of
[131]
FOLFIRI and bevacizumab treatment. O’Connor et al
reported that the variance of CRC liver metastases
shrinkage after bevacizumab and FOLFOX-6 treatment
was mainly explained by the median values of ve,
tumor enhancing fraction (EF), and microvascular
[132]
uniformity. Miyazaki et al reported that DCE-MRI-
derived liver distribution volume and tumor distribution
volume were significantly increased in liver metastases
with good response to radiolabeled octreotide; low
pretreatment values of liver distribution volume and
high tumor arterial flow fraction were associated with
better response.
Pancreatic tumors
DWI has been tested for treatment response evaluation
of pancreatic tumors: therapy seems to increase ADC
[133]
values. Niwa et al reported ADC differences among
patients with advanced pancreatic cancer treated
with gemcitabine: in particular, significant differences
between patients with progressive disease and those
with stable disease were found at 3- and 6-mo follow-
up. Tumor progression rate was significantly higher in
patients with low ADC values than in those with higher
[134]
values. Cuneo et al reported a significant correlation
between pre-treatment mean ADC values of surgically
resected PDACs and the amount of tumor cell
destruction after chemoradiation evaluated on surgical
specimens, with a Pearson correlation coefficient of
0.94 (P = 0.001): the mean pre-treatment ADC value
-3 2
was 1.61 × 10 mm /s in responding patients (> 90%
-3 2
tumor cell destruction) compared to 1.25 × 10 mm /s
in non-responding patients (> 10% viable tumor).
[135]
Regarding PanNETs, Yao et al reported that
bevacizumab was associated with a 44% decrease in
BF in patients with low-to intermediate grade tumors;
the addition of everolimus induced a further 29% BF
decrease. Everolimus alone was associated with 13%
increase in MTT. Pretreatment PS (P = 0.009), post-
treatment MTT (P = 0.003), percent reduction in BF
(P = 0.03), and percent reduction in BV (P = 0.002)
were associated with high percent reduction in tumor
diameters. Such perfusion changes occurred early
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 De Robertis R et al . Functional imaging in hepato-bilio-pancreatic tumors
after treatment start and might be used as functional
biomarkers of response to bevacizumab or everolimus
treatment.
CONCLUSION
Literature data reveal that DWI can provide prognostic
stratification of HCCs and PDACs, as DWI findings may
reflect “adverse” pathological features associated with
poor clinical outcome and prognosis. ADC values are
generally low in poorly differentiated lesions, although
different results have been reported regarding the
direct correlation of ADC values and the pathological
grade. Perfusion imaging techniques can theoretically
depict microvascular changes related to dedifferen­
tiation of HCCs and PDACs, but poor and controversial
results have been reported.
Overall, it seems that functional radiological
techniques find their most important applications in
PanNETs: both DWI and perfusion imaging methods
provide indirect information on their clinical behavior
and improve their staging.
Functional imaging techniques can predict treat­
ment outcome and assess response of primary and
metastatic hepatic tumors to loco-regional therapies,
particularly TACE: ADC increase seems to be asso­
ciated with good clinical outcome.
Perfusion imaging can be of value in the post-
treatment assessment of patients treated with tyrosine
kinases inhibitors: DCE-MRI and pCT can distinguish
responders from non-responders using DCE-imaging.
Functional radiological techniques are therefore
reliable and useful to evaluate patients with hepatic and
pancreatic tumors; these “new imaging” techniques
could be therefore considered and -whenever possible-
adopted as a part of CT/MRI examination protocols.
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P- Reviewer: Ji Y, Lim SM, Sun XJ S- Editor: Qi Y L- Editor: A
E- Editor: Ma S
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